The invention relates to novel 1-(p-thienylbenzyl)imidazoles of formula (I), 
which are potent agonists of angiotensin (1-7) receptors and, because of the production land release of the vasorelaxant, antithrombotic, and cardio-protective messengers cyclic 3xe2x80x2,5xe2x80x2-guanosine monophosphate (cGMP) and nitrogen monoxide (NO) associated with the stimulation of these receptors on endothelial cells, are valuable pharmaceuticals for the treatment and prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and of arterial and venous thrombosis.
EP-A 512675 and WO 94/27597 describe thienylbenzyl-substituted imidazoles as angiotensin II receptor-antagonists and their use for the treatment of hypertension, cardiac insufficiency, migraine, Alzheimer""s disease, and as antidepressants. Moreover, thienylbenzyl-substituted imidazopyridines are disclosed in EP-A 513979 as antagonists of angiotensin II receptors and their use for the treatment of hypertension, cardiac insufficiency, migraine, and Alzheimer""s disease, and in U.S. Pat. No. 5,444,067 as angiotensin II agonists and their use for the treatment of hypotension and of hypoaldosteronism. In addition, in EP-A 534706 thienylbenzyl-substituted quinazolinones and pyridopyrimidones and in EP-A 510812 thienylbenzyl-substituted triazoles are disclosed as antagonists of angiotensin II receptors.
The 1-(p-thienylbenzyl)imidazoles of formula (I) described here and their use as agonists of angiotensin (1-7) receptors are in this case neither described, anticipated, nor suggested in the applications mentioned.
Surprisingly, it has been found that 1-(p-thienylbenzyl)imidazoles of formula (I) have a marked action on angiotensin (1-7) receptors and mimic the biological action of the effector hormone angiotensin (1-7).
The invention thus relates to compounds of formula (I) 
in which:
R(1) is
(1) halogen;
(2) hydroxyl;
(3) (C1-C4)-alkoxy;
(4) (C1-C8)-alkoxy, wherein 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably by O;
(5) (C1-C4)-alkoxy, substituted by a saturated cyclic ether such as tetrahydropyran or tetrahydrofuran;
(6) Oxe2x80x94(C1-C4)-alkenyl;
(7) Oxe2x80x94(C1-C4)-alkylaryl; or
(8) aryloxy, unsubstituted or substituted by a substituent selected from halogen, (C1-C3)-alkyl, (C1-C3)-alkoxy, and trifluoromethyl;
R(2) is
(1) CHO;
(2) COOH; or
(3) COxe2x80x94Oxe2x80x94(C1-C4)-alkyl;
R(3) is
(1) (C1-C4)-alkyl; or
(2) aryl;
R(4) is
(1) hydrogen;
(2) halogen; or
(3) (C1-C4)-alkyl;
X is
(1) oxygen; or
(2) sulfur;
Y is
(1) oxygen; or
(2) xe2x80x94NHxe2x80x94;
R(5) is
(1) hydrogen;
(2) (C1-C6)-alkyl; or
(3) (C1-C4)-alkylaryl;
where R(5) can only be hydrogen if Y has the meaning mentioned under (2); and
R(6)
(1) (C1-C5)-alkyl;
in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof;
wherein R(1) may not be halogen when R(2) is COOH or COxe2x80x94Oxe2x80x94(C1-C4)-alkyl.
The term alkyl means, if not stated otherwise, straight-chain or branched saturated hydrocarbon radicals. This also applies to substituents derived therefrom such as alkoxy or the radical S(O)m-alkyl. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Examples of alkoxy are methoxy, ethoxy, n-propoxy, and isopropoxy. Examples of aryloxy are phenoxy or naphthoxy. Phenoxy is preferred.
Alkenyl represents mono- or polyunsaturated hydrocarbon radicals in which the double bonds can be situated in any desired positions. Examples of alkenyl are vinyl, prompenyl, and butenyl.
Halogen represents fluorine, chlorine, bromine, or iodine, preferably chlorine or fluorine.
Aryl represents phenyl or naphthyl, preferably phenyl.
In substituted aryl radicals, the subsfituents can be situated in any desired position relative to one another.
Examples of arylalkyl radicals are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, and naphthylbutyl.
If compounds of formula (I) contain one or more acidic or basic groups, the invention also encompasses the corresponding physiologically tolerable salts, in particular the pharmaceutically utilizable salts. Thus, compounds of formula (I) which carry acidic groups, such as one or more COOH groups, can be present, for example, as their alkali metal salts, preferably sodium or potassium salts, or as their alkaline earth metal salts, e.g., calcium or magnesium salts, or as ammonium salts, e.g., as salts with ammonia or organic amines or amino acids. Compounds of formula (I) which carry one or more basic, i.e., protonatable, groups, can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, or gluconates. If compounds of formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms outlined, internal salts, so-called betaines. Salts can be obtained from compounds of formula (I) by customary processes, for example by combination with an acid or base in a solvent or dispersant or otherwise from other salts by anion exchange.
Physiologically tolerable salts of compounds of formula (I) are to be understood, for example, as also meaning organic and inorganic salts, such as are described in Remington""s Pharmaceutical Sciences (17th Edition (1985) 1418). On account of the physical and chemical stability and the solubility, preferred acidic groups are, inter alia, sodium, potassium, calcium, and ammonium salts; preferred basic groups are, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid, or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, and p-toluenesulfonic acid.
The present invention furthermore comprises solvates of compounds of formula (I), for example hydrates or adducts with alcohols, and also derivatives of compounds of formula (I) such as, for example, esters, and prodrugs and active metabolites.
Preferred compounds of formula (I) are those in which
R(1) is
(1) chlorine;
(2) hydroxyl;
(3) methoxy, ethoxy, or propyloxy;
(4) methoxyethoxy or methoxypropoxy;
(5) allyloxy; or
(6) phenoxy;
R(4) is
(1) hydrogen; or
(2) chlorine;
R(5) is
(1) hydrogen; or
(2) (C1-C4)-alkyl;
R(6) is
(1) n-propyl or 2-isobutyl;
and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Compounds of formula (I) are furthermore preferred in which
R(1) is
halogen, preferably chlorine, (C1-C4)-alkoxy, preferably methoxy, ethoxy, or propyloxy, particularly preferably methoxy, or (C1-C8)-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably O, preferably methoxyethoxy or methoxypropoxy;
R(2) is
CHO;
R(3) is
aryl, preferably phenyl;
R(4) is
halogen, preferably chlorine, or hydrogen;
R(5) is
(C1-C6)-alkyl, preferably methyl, ethyl, propyl, or butyl;
R(6) is
(C1-C5)-alkyl, preferably ethyl, propyl, or butyl;
X is
oxygen;
Y is
oxygen or xe2x80x94NHxe2x80x94;
in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Compounds of formula (I) are very particularly preferred when these are compounds of formula (II) 
in which the radicals R(1), R(4), R(5), R(6), and Y have the abovementioned meaning, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Preferred compounds of formula (I) are also those in which R(1) is (C1-C4)-alkoxy or (C1-C8)-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably O, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Particularly preferred compounds of formula (I) are also those in which R(2) is CHO, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Preferred compounds of formula (I) are furthermore those in which X is O, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Particularly preferred compounds of formula (I) are:
4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamino)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5-isobuty-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbofnylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formylmethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole sodium salt;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole L-lysine salt; or
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole tris(hydroxymethyl)aminomethane salt.
The invention furthermore relates to processes for the preparation of compounds of formula (I), comprising the following reaction:
a) Providing 4-chloro-5-formylimidazole derivatives of formula (III), 
xe2x80x83in which R(3) has the abovementioned meaning and whose preparation is described, for example, in Chem. Pharm. Bull. 24 (1976) 960-969, and reacting with p-bromobenzyl bromides of formula (IV), 
xe2x80x83in which R(4) is as defined above, resulting in the formation of compounds of formula (V) 
xe2x80x83in which R(3) and R(4) have the abovementioned meanings, where the alkylation can be carried out in the presence of an organic or inorganic base such as, for example, triethylamine, K2CO3, or Cs2CO3 in an inert solvent such as, for example, DMF. Compounds of formula (IV) are commercially obtainable or can be prepared by methods known per se.
b) Compounds of formula (V) can be reacted with thiophene-3-boronic acids of formula (VI) 
xe2x80x83in which R(6) is as defined above and whose preparation is disclosed in EP-A 512 675, to give 1-(p-thienyl)imidazoles of formula (VII) 
xe2x80x83in which R(3), R(4), and R(6) are as defined above. This Suzuki-type cross-coupling reaction is preferably carried out using palladium(II) acetate and triphenylphosphine or tetrakistriphenyjphosphinepalladium as catalysts in the presence of a base such as, for example, cesium or potassium carbonate, for example, in solvent mixtures of ethanol and toluene at temperatures up to the boiling point of the solvents; corresponding reactions are described, for example, in Synthetic Commun. 11 (1981) 513, J. Med. Chem. 38 (1995) 2357-2377, and Liebigs Ann. (1995) 1253-1257.
c) Compounds of formula (VII) can be converted by removal of the tert-butyl protective group into sulfonamides of formula (VIII) 
xe2x80x83in which R(3), R(4), and R(6) are as defined above. This removal is preferably carried out by treatment of compounds of formula (VII) with organic acids such as, for example, concentrated trifluoroacetic acid in the presence of anisole.
d) Compounds of formula (VIII) can be converted by substitution of the chlorine atorm in position 4 of the imidazole ring into compounds of formula (IX) 
xe2x80x83in which R(3), R(4), and R(6) are as defined above, and R(1)xe2x80x2 represents the radicals mentioned under (2) to (8) for R(1). This substitution of the chlorine atom can be carried out in this case, for example, by treatment of compounds of formula (VIII) with alkoxides formed in situ by the action of bases such as NaOH or NaH on the alcohols generally used as solvents, such as, for example, methanol, ethanol, or ethylene glycol monomethyl ether, at temperatures of from 50xc2x0 C. up to the boiling point of the alcohols.
Alternatively, compounds of formula (IX) in which R(1)xe2x80x2 is (C1-C4)-alkoxy can be converted via an ether cleavage, by treatment preferably of the methoxy ethers of formula (IX) with concentrated acids such as HI and HBr, or with Lewis acids such as BF3, BCl3, BBr3, AlCl3, or their etherates, preferably with BBr3, in an inert solvent such as, for example, CH2Cl2, into the corresponding phenols, which can then be reacted by processes known per se with the suitably substituted halides such as, for example, 2-bromoethyl methyl ether or benzyl bromide in the presence of a base in an inert solvent at temperatures up to the boiling point of the solvent.
The corresponding diphenyl ether compounds can be obtained from the reaction of the phenols of formula (IX) with boronic acids such as, for example, phenylboronic acid or 4-methoxyphenylboronic acid in the presence of copper catalysts such as, for example, Cu(OAc)2. Appropriate reactions are described, for example, in Tetrahedron Lett. 39 (1998) 2937-2940.
e) From sulfonamides of formula (IX), it is possible by reaction with R(5)-substituted chloroformic acid esters to prepare sulfonylurethanes of formula (Ia) 
xe2x80x83in which R(1), R(2), R(3), R(4), and R(6) are as defined above, and R(5) only has the meaning mentioned under (2) and (3). This reaction can be carried out in the presence of a base such as, for example, pyridine, and of an acylation accelerator, such as 4-pyrrolidinopyridine, at temperatures from room temperature (RT) to 150xc2x0 C., but preferably at RT.
f) From sulfonamides of formula (IX), it is possible by treatment with R(5)-substituted isocyanates or isothiocyanates to obtain sulfonylureas of formula (Ib) 
xe2x80x83in which R(1), R(2), R(3), R(4), R(6), and X are as defined above, and R(5) only has the meaning mentioned under (2) and (3). The reaction with R(5)-substituted isocyanates and isothiocyanates can be carried out in the presence of a base in an inert solvent at temperatures from RT to 150xc2x0 C.
Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, or potassium tert-butoxide. Suitable inert solvents are ethers such as THF, dioxane, ethylene glycol dimethyl ether, or diglyme, ketones such as acetone or butanone, nitrites such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as DMF or N-methylpyrrolidone, hexamethylphosphoramide, sulfoxides such as DMSO, and hydrocarbons such as benzene, toluene, or xylenes. Furthermore, mixtures of these solvents with one another are also suitable.
Sulfonylureas of formula (Ib) may also be prepared by reaction of amines R(5)-NH2 with sulfonyl isocyanate derivatives that result from sulfonamides of formula (IX), for example, by treatment with phosgene or a phosgene substitute such as triphosgene.
Alternatively, sulfonylureas of formula (Ib) can be prepared by reaction of sulfonamides of formula (IX) with 2,2,2-trichloroacetamide derivatives of a suitable amine R(5)-NH2 in the presence of a base in an inert, high-boiling solvent such as, for example, DMSO or from the corresponding sulfonylurethane of formula (Ia) accessible by reaction with ethyl chloroformate by action of the corresponding amine R(5)-NH2 in an inert, high-boiling solvent such as, for example, toluene, at temperatures up to the boiling point of the respective solvent, which is described, for example, in J. Med. Chem. 38 (1995) 2357-2377, and in Bioorg. Med. Chem. 5 (1997) 673-678.
N-Unsubstituted sulfonylureas of formula (Ib), in which R(5) is hydrogen, can be prepared by hydrolysis of sulfonamidonitriles resulting after reaction of sulfonamides of formula (IX) with cyanogen bromide in the presence of K2CO3 in acetonitrile with sulfuric acid at temperatures of from xe2x88x9210xc2x0 C. to 0xc2x0 C.
By methods known per se, such as are described in the literature (e.g., in the standard works such as Houben-Weyl, Methoden der Oranischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley and Sons, Inc., New York; or Larock, Comprehensive Organic Transformations, VCH, Weinheim), it is possible by oxidation of the aldehyde group in compounds of formula (I) to prepare the corresponding carboxylic acids or carboxylic acid esters of formula (I).
The invention also relates to compounds of formula (X) 
in which R is hydrogen or a suitable protective group such as, for example, (C1-C6)-alkyl, preferably tert-butyl, and the radicals R(1), R(2), R(3), R(4), and R(6) are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Compounds of formula (X) are valuable intermediates for the preparation of compounds of formula (I) according to the invention. In addition, compounds of formula (X) have a high affinity for the angiotensin (1-7) receptor and can be used as angiotensin (1-7) receptor agonists and thus as pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by a reduced production and/or release of the vasorelaxant, anti-thrombotic, and cardioprotective messengers cyclic 3xe2x80x2,5xe2x80x2-guanosine monophosphate (cGMP) and nitrogen monoxide (NO). For example, these compounds are used for the treatment and/or prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or. endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
The vascular endothelium is a metabolically active organ with a large number of regulatory functions, that is capable of the synthesis and release of vasoactive substances. A dysfunction of the endothelial layer lining the vessel is correlated with the pathogenesis of various cardiovascular disorders such as arteriosclerosis and hypertension (Eur. J. Clin. Invest. 23 (1993) 670-685). An endothelial dysfunction is characterized by a reduced synthesis and/or release of the vasorelaxant, vasoprotective, antithrombotically, and antiproliferatively active messengers NO and cGMP, which play an important role in the prevention and regression of vascular remodeling and arterial hypertension. Substances that are able to stimulate the synthesis and release of these messengers are therefore valuable pharmaceuticals for the treatment of all diseases that are characterized by endothelial dysfunction.
A large number of published experiments confirm that a degradation product of therenin-angiotensin system, the heptapeptide angiotensin (1-7), is a potent, endogenous effector hormone of the renin-angiotensin system (Hypertension 12 (Suppl. III) (1991) III-126-III-133), whose biological action is caused by the stimulation of specific receptors, which preferably bind angiotensin (1-7) (Peptides 14 (1993) 679--684; Hypertension 29 (part 2) (1997) 388-393). This action is in many cases directed against that of the vasoconstrictory hormone angiotensin II or opposes this in a counter regulatory manner (Hypertension 30 (part 2) (1997) 535-541; Regulatory Peptides 78 (1998) 13-18).
Hypertension 19 (Suppl. II) (1992) II-49-II-55, and Am. J. Cardiol. 82 (1998) 17S-19S, showed that angiotensin (1-7) stimulated the production and/or the release of NO/cGMP and the prostaglandins E2 and I2, which is not blocked by pretreatment with AT1 and AT2 receptor antagonists.
An endothelium-dependent relaxation of intact coronary arteries of dogs and pigs was described in Hypertension 27 (part 2) (1996) 523-528, and an endothelium-dependent relaxation of intact, KCl-precontracted rat aortas by angiotensin (1-7), which is not affected by AT1 receptor antagonists, was described in J. Cardiovasc. Phermacol. 30 (1997) 676-682.
The hypotensive action of angiotensin (1-7) in spontaneously hypertensive rats on continuous infusion by means of an osmotic minipump was shown in Peptides 14 (1993) 679-684, and in Am. J. Physiol. 269 (1995) H313-H319, angiotensin (1-7) in normotensive rats having no action on the blood pressure in the same dose. Complementary to these investigations, it was demonstrated in Hypettension 31 (1998) 699-705, that the infusion of an angiotensin (1-7) antibody increases the mean arterial blood pressure in conscious, spontaneously hypertensive rats which had been pretreated with lisinopril and losartan.
Am. J. Hypertension 11 (1998) 137-146, showed that in persons having essential hypertension, markedly lower plasma levels of angiotensin (1-7) are detectable than in normotensive persons.
The anti-proliferative action of angiotensin (1-7) on vascular smooth muscle cells was confirmed in Hypertension 28 (1996) 104-108, and the inhibition of the proliferation of smooth muscle cells after vascular tissue damage was confirmed in Hypertension 33 (part II) (1999) 207-211.
Moreover, angiotensin (1-7) in sodium chloride-loaded, anesthetized normotensive Wistar rats also showed renal effects such as increased natriuresis and diuresis (Am. J. Physiol. 270 (1996) F141-F147).
Compounds of formula (I) described here are potent, nonpeptide agonists of the postulated angiotensin (1-7) receptors, which are preferably located in the vessels (including endothelium), in the kidney, in the CNS, and in the heart. They therefore mimic the biological action of the peptide hormone angiotensin (1-7) directed against angiotensin II, described above, which is to be attributed to the production and/or release of cGMP and NO from the endothelium, without in this case being subject to the rapid metabolic degradation of this hormone. Because of the stimulation of the production and/or release of these vasorelaxant, antithrombotic, and cardioprotective messengers, angiotensin (1-7) receptor agonists of formula (I) described are valuable pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused, or at least partly caused, by a reduced production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO. These compounds can thus be employed, for example, in the treatment and/or prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
The stimulation of endothelial angiotensin (1-7) receptors by agonists of formula (I) causes the release of vasodilatory and organ-protective autacoids. This mechanism differs here from that of ACE inhibition and AT1 receptor blockade by the avoidance either of lowered tissue angiotensin II (in the case of ACE inhibitors) or of effects which still cannot be estimated at present, which are associated with increased ANG II plasma values (in the case of AT1 receptor antagonists).
Compounds of formula (I) or their physiologically tolerable salts can thus be used in animals, preferably in mammals, and in particular in humans, as pharmaceuticals either on their own, as mixtures with one another or together with other active compounds, in particular in the form of pharmaceutical preparations. The present invention therefore relates to the use of compounds of formula (I) and/or their physiologically tolerable salts for the production of a medicament for the therapy or prophylaxis of the abovementioned syndromes, and to pharmaceutical preparations which contain an efficacious dose of at least one compound of formula (I) and/or of a physiologically tolerable salt thereof as active constituent in addition to at least one customary, pharmaceutically innocuous vehicle and/or excipient. The pharmaceutical preparations can be intended for enteral or parenteral use, and normally contain 0.5 to 90% by weight of at least one compound of formula (I) and/or a physiologically tolerable salt thereof. The amount of active compound of formula (I) and/or a physiologically tolerable salt thereof in the pharmaceutical preparations is in general 0.2 to 500 mg, preferably 1 to 300 mg.
Pharmaceuticals employed according to the invention, which contain at least one compound of formula (I), and/or a physiologically tolerable salt thereof, can be administered enterally, for example orally or rectally, in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, solutions such as aqueous, alcoholic, or oily solutions, juices, drops, syrups, emulsions, or suspensions. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly, or intravenously in the form of injection solutions or infusion solutions. Further possible administration forms are, for example, percutaneous or topical administration, in the form of ointments, creams, pastes, lotions, gels, sprays, powders, foams, aerosols, or solutions, or use in the form of implants.
The pharmaceutical preparations employed according to the invention can be prepared by the known standard processes for the production of pharmaceutical preparations. For this, at least one compound of formula (I) and/or a physiologically tolerable salt thereof are brought together with at least one solid or liquid pharmaceutical vehicle and/or additive or excipient, and, if desired, in combination with at least one other pharmaceutical active compound having therapeutic or prophylactic action, for example cardiovascular-active pharmaceuticals such as, for example, calcium antagonists, ACE inhibitors, AT1 receptor antagonists, NO donors, endothelin receptor antagonists, K+ channel openers, phosphodiesterase inhibitors, diuretics, or xcex1- and xcex2-blockers, into a suitable administration form or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
Possible vehicles are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral (for example intravenous) administration or topical application and do not react with active compounds of formula (I), for example water, vegetable oils, alcohols such as ethanol, isopropanol, or benzyl alcohol, 1,2-propanediol, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly, acetonitrile, dimethylformamide, and dimethylacetamide. In particular, pharmaceutical forms such as tablets, sugar-coated tablets, capsules, solutions, preferably oily or aqueous solutions, syrups, juices, or drops. Furthermore, suspensions or emulsions are used for oral and rectal administration. Mixtures of two or more vehicles can also be employed, for example, mixtures of two or more solvents, in particular also mixtures of at least one organic solvent with water. As additives or excipients, the pharmaceutical preparations can contain, for example, stabilizing and/or wetting agents, emulsifiers, salts, for example for affecting the osmotic pressure, lubricants, preservatives, colorants and flavorings, and/or aromatizers and buffer substances. If desired, they can also contain at least one further active compound, for example at least one vitamin. Compounds of formula (I) and/or their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations. Liposomal preparations are also particularly suitable for topical application.
The dose of at least one active compound of formula (I) to be administered and/or of a physiologically tolerable salt thereof in the case of use according to the invention depends on the individual case and is to be tailored to the individual conditions as customary for an optimal action. Thus it depends on the nature and severifty of the illness to be treated, and on the sex, age, weight, and individual responsiveness of the human or animal to be treated, on the potency and duration of action of the compounds employed, on whether the therapy is acute or chronic or prophylaxis is carried out, or on whether further active compounds are administered in addition to compounds of formula (I). In general, a dose range for the treatment of the abovementioned syndromes in humans of approximately 0.1 mg to approximately 100 mg per kg per day on administration to an adult weighing about 75 kg is adequate to achieve the desired action. A dose range of 1 to 20 mg per kg per day (in each case mg per kg of body weight) is preferred. The daily dose can be administered here as an individual dose or can be divided into a number, for example, 1, 2, 3, or 4, of individual doses. It can also be administered continuously. If appropriate, depending upon individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated. Pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 300 mg, of at least one active compound of formula (I) and/or a physiologically tolerable salt thereof.
The invention also very generally comprises the use of preferably nonpeptide compounds which bring about a stimulation of angiotensin (1-7) receptors which are located, for example, in the vessels (including endothelium), in the kidney, in the CNS, and in the heart, as pharmaceuticals, preferably for oral administration, or for use as substances which stimulate the production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO, and as pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by a reduced production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO, in particular for the treatment and prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
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The invention is illustrated by the examples below, without being restricted to these.